Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An important role for the p53 gene in osteogenic sarcomas has been imputed by identification of somatically acquired gene alterations in human osteosarcomas and by the development of osteosarcomas in p53 transgenic mice. To study the involvement of p53 in radiation-induced osteosarcomagenesis, we have investigated gene alterations and expression of p53 in radiation-induced murine osteosarcomas and tumor-derived cell lines. Eighteen of 31 tumors and 8 of 9 cells lines showed alterations in the p53 gene region, or elevated levels of p53 RNA. Expression of the osteoblast marker gene bone gla protein was substantially reduced in tumors which simultaneously showed high steady-state levels of p53 RNA. Our data indicate that p53, in addition to its function in regulating DNA synthesis, may be involved in the control of osteogenic differentiation in osteosarcomagenesis.
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PMID:Elevated p53 RNA expression correlates with incomplete osteogenic differentiation of radiation-induced murine osteosarcomas. 173 May 19

p53 is a 53-kDa nuclear protein that is associated with malignant transformation in several tumor model systems. In a survey of 134 human carcinomas, sarcomas, leukemias, and lymphomas obtained at surgery or from peripheral blood, we found rearrangements of the p53 gene only in osteogenic sarcomas (3 of 6 osteogenic sarcomas examined). Normal tissue from one of these patients had an unrearranged gene, indicating that the genetic abnormality in the tumor was acquired. Two of the sarcomas with rearranged genes expressed levels of p53 protein that were elevated relative to other tumors. Rearranged p53 genes were also found in human osteogenic sarcoma cell lines.
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PMID:Rearrangement of the p53 gene in human osteogenic sarcomas. 282 72

Transgenic mice carrying the SV40 early region fused to the Drosophila hsp70 promoter developed smooth muscle and bone neoplasms. The smooth muscle tumors appeared in aged mice and were preferentially located on the muzzle or eyelids. Multiple neoplasms were often present and each appeared to be an independent proliferation. In contrast, the bone tumors typically developed in the petrous ridge and had all the features of osteogenic sarcomas, displaying distant metastasis and invasion of the brain. Cells in both types of tumors exhibited nuclear expression of SV40 T antigen. Mice homozygous for the transgene had a shorter latency for appearance of smooth muscle tumors and developed osteosarcomas more frequently than hemizygous mice. This model system implicates the cellular T antigen-binding proteins, such as Rb and p53, in the pathogenesis of bone and soft tissue neoplasms in mice.
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PMID:Smooth muscle and bone neoplasms in transgenic mice expressing SV40 T antigen. 808 93

Since multistage carcinogenesis is frequently associated with the loss of suppressor gene activity, and since in over 90% of cases of nasopharyngeal carcinoma (NPC) p53 alterations are not involved [Sun, Y., Hegamyer, G.H., Cheng, Y.-J., Hildesheim, A., Chen, J.-Y., Chen, I.-H., Cao, Y., Yao, K.-T. & Colburn, N.H. (1992). Proc. Natl. Acad. Sci. USA, 89, 6516-6520] we investigated the possible involvement of the inactivation of the retinoblastoma susceptibility gene (RB) in nasopharyngeal carcinogenesis. We analysed the expression, gross structure and possible point mutation of the RB gene in an NPC cell line as well as seven NPC biopsies obtained from seven patients. The NPC cell line expresses the RB gene with a normal size and abundance, as assayed by reverse transcriptase polymerase chain reaction (RT-PCR) and Northern hybridization. No point mutation was detected in two independent E1A/large T-binding regions, which are the common sites for mutations in the RB gene. NPC biopsies also showed no point mutations at four exon-intron boundaries at which point mutations have been reported in other human carcinomas. The biopsies and cell line had no deletions in the promoter region of the gene and showed no gross deletions or rearrangements. Taken together, we conclude that, in contrast to multistage carcinogenesis leading to human retinoblastoma, osteogenic sarcomas and carcinomas of lung, breast, bladder and prostate, nasopharyngeal carcinogenesis appears unlikely to involve RB gene alterations.
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PMID:Nasopharyngeal carcinoma shows no detectable retinoblastoma susceptibility gene alterations. 843 63

Alterations in the p53 tumor suppressor gene have been implicated in the genesis and/or progression of the majority of human cancers, including osteosarcoma. Stabilization of the protein by mutation or interaction with other proteins prolongs its half-life, rendering it detectable by immunohistochemistry. Osteosarcoma is the most common primary canine bone tumor and is characterized by frequent early metastases. Multilobular tumors of bone involve primarily flat bones of the head and are low-grade malignancies with lower metastatic potential. The objectives of this study were to determine the prevalence of p53 protein overexpression in 106 osteogenic tumors of dogs using an indirect immunohistochemical method and to compare p53 overexpression between tumors with different clinical behavior. A polyclonal p53 antibody (CM-1) served as the primary antibody. Tumors were scored based upon an estimate of the percentage of tumor cells stained. Significant differences in the prevalence of overexpression were observed between osteosarcomas (72%) and multilobular tumors of bone (20%, P = 0.0020). Osteosarcomas of the appendicular skeleton had a significantly higher prevalence of p53 overexpression (84%) than did osteosarcomas of the axial skeleton (56%, P = 0.0060). Our results show that p53 tumor suppressor protein is overexpressed in the majority of canine osteosarcomas. The higher prevalence of overexpression in osteosarcomas versus multilobular tumors of bone and in osteosarcomas of the appendicular skeleton versus those of the axial skeleton suggests that alterations in p53 expression correlate with highly aggressive tumor behavior.
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PMID:p53 tumor suppressor protein overexpression in osteogenic tumors of dogs. 880 15

Studies were carried out to determine the effects of introducing p53 using an adenovirus gene transfer vector into p53 null human Saos-2 osteogenic carcinoma cells. Expression of p53 led to cell death within 30-40 h. The morphology of these cells as determined by electron microscopy indicated that death was by apoptosis. Such death was significantly reduced in Saos-2 variants that express high levels of the Bcl-2 suppressor of apoptosis. It was also found that the E1B-55 kDa protein of human adenovirus type 5, which was known to bind and inactivate p53, blocks Saos-2 cell death following expression of p53. These results thus directly demonstrate that this viral protein is able to inhibit p53-induced apoptosis.
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PMID:Expression of p53 in Saos-2 osteosarcoma cells induces apoptosis which can be inhibited by Bcl-2 or the adenovirus E1B-55 kDa protein. 895 32

p53 protein regulates cell cycle progression and its absence will result in unlimited cell divisions required for immortalization of cells. Immortalized osteoblastic cell lines were established from p53 null mouse calvariae of normal phenotype. The clonal murine cell lines demonstrated osteoblastic phenotype as exemplified by alkaline phosphatase enzyme activity. They also express bone morphogenetic protein 2 (BMP2) mRNA. Addition of recombinant BMP2 to these cells dramatically increased the alkaline phosphatase activity in a dose dependent manner. In the absence of BMP2 these cells do not undergo osteoblastic differentiation. Treatment of these cells with recombinant bone morphogenetic protein 2 stimulated differentiated osteoblast formation, as determined by mineralized nodule formation. Thus, these immortalized cells in culture represent osteoblast progenitors that lack p53 protein and respond to osteogenic stimuli. These cell lines offer a model system to study the role of p53 in osteoblastic differentiation and programmed cell death. Also these cells will be useful in studying the effects of p53 on transcriptional regulation of osteoblast specific gene expression.
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PMID:Clonal osteoblastic cell lines from p53 null mouse calvariae are immortalized and dependent on bone morphogenetic protein 2 for mature osteoblastic phenotype. 907 Feb 48

Epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I) receptors are implicated in the development and progression of several malignancies including osteogenic and soft tissue sarcomas (STS). To determine a role for ligand-mediated receptor activation in sarcoma progression, the relative expression and function of EGF-R, IGF-I-R, and several other molecular determinants implicated in the progression of mesenchymal neoplasms were evaluated in human sarcoma cells established from surgical specimens of primary and metastatic tumors. mRNA blot analyses demonstrated the expression of c-Met, p53, and MDM2-specific transcripts. Western blot analyses confirmed the production of high levels of p53 protein; however, minimal levels of MDM2 and c-Met proteins were detected. Analysis of STS cells #23, #26, and #50 originating from an unclassified sarcoma lung metastasis, a malignant fibrous histiocytoma lung metastasis, and a dedifferentiated chondrosarcoma, respectively demonstrated high steady-state levels of EGF-R and IGF-I-R mRNA transcripts and protein correlating with receptor-specific tyrosine kinase activity and autophosphorylation in response to ligand. Treatment of these STS cells with EGF resulted in a >5 fold increase in DNA synthesis and mitogenesis compared with untreated controls. In contrast, treatment with IGF-I showed a variable STS growth response correlating with the origin of the tumor. These data support the involvement of EGF-R and IGF-I-R in the growth and metastasis of human soft tissue sarcoma and may offer new targets for therapeutic intervention in the management of this disease.
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PMID:Epidermal growth factor receptor and insulin-like growth factor-I receptor expression and function in human soft-tissue sarcoma cells. 945 58

There are several common themes that are emerging from our expanding knowledge about the inherited bone marrow failure syndromes. Patients have a spectrum of birth defects, which are relatively characteristic for each syndrome. but overlap in features such as poor growth. radial ray anomalies, and involvement of skin, eyes, renal, cardiac, skeletal, and other organs. Within each syndrome the composition and severity of the physical phenotype varies widely, and it may require the astute observer to make the correct diagnoses in the milder cases. There is also a wide spectrum to the hematologic picture. These range from single cytopenias such as DBA, SCN, and TAR, which do not develop pancytopenia, to SD and Amega patients who begin with deficiency of a specific single lineage, but evolve to aplastic anemia, to patients with FA or DC, who may present with a deficiency of any one of the cell lines, but almost inevitably end up with full-blown aplastic anemia. Acute myeloid leukemia has been observed in FA, DBA, DC, SD, SCN, and Amega, although not yet in TAR patients. MDS has also been reported in all of the same disorders as AML, although whether it is a preleukemic condition or an independent bone marrow dyspoiesis is not yet clear. Solid tumors are also now appearing in patients whose underlying disease involves hematopoiesis and physical development. These tumors occur at much younger ages than in the general population, in patients who do not appear to have the usual risk factors, and have patterns that are characteristic to the syndrome, such as head and neck and gynecologic cancers in FA and DC, and osteogenic sarcomas in DBA. The other syndromes have not yet been reported to have a propensity for solid tumors. Several genes have been identified that are mutant in some of the syndromes, although the pathophysiology is still not entirely clear. The inheritance patterns include X-linked recessive, autosomal dominant, autosomal recessive, and even mitochondrial. The FA gene products appear to cooperate, and are important in the pathways involved in response to DNA damage. However, the role of this pathway in developmental defects, hematopoietic failure, and the specific malignancies in FA is not fully elucidated. The DC gene products are important for maintenance of telomere length, which may have relevance to development of aplastic anemia and malignancies, but the relation to the physical phenotype is less apparent. The role of mutations in c-mpl in Amega is more straightforward. since the gene codes for the receptor for thrombopoietin. which is the hormone required for megakaryocyte and platelet development; patients with mutant c-mpl do not have birth defects. The role of mutations in RPS19 in erythropoiesis or developmental defects in DBA patients is not obvious, and the increased frequency of osteogenic sarcomas suggests that at least that subset of patients may have a mutant tumor suppressor gene (such as p53, the mutant gene in Li-Fraumeni syndrome) [68]. Although patients with SCN have mutations in neutrophil elastase, patients with similar mutations may have relatively benign cyclic neutropenia, or may even have normal neutrophil levels [69,70]. The mitochondrial gene deletions in Pearson's Syndrome result in variable degrees of acidosis, and varied organ involvement due to heteroplasmy. Thus, the disorders included under the rubric "inherited bone marrow failure syndromes" have clinical. hematologic, oncologic, and genetic diversity.
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PMID:Bone marrow failure syndromes in children. 1243 Jun 21

Three clonal cell lines (MMR14, MMR17, and MMR32) were established from the costal cartilage derived from p53-/- mice. Expression profiles of cartilage-related molecules in MMR14 and MMR17 were compatible with those in cells of the hypertrophic zone. Prolonged in vitro culture induced the expression of calcification-related genes in both cell lines, but calcified nodules were observed only in MMR14. The expression profile of cartilage-related molecules in MMR32 was compatible with that of cells in the perichondrium, with high expression levels of decorin, bone morphogenetic protein-3, and parathyroid hormone-related peptide (PTHrP). When MMR14 was co-cultured with an equal amount of MMR32 without direct contact, the nodule formation was completely inhibited, whereas no such inhibition was observed when MMR14 was co-cultured with MMR17, indicating that soluble factors produced by MMR32 were responsible for the inhibition. Blocking the effects of PTHrP by either antagonizing peptide or neutralizing antibody against PTHrP failed to rescue the inhibitory effects of MMR32, and no increase of the cyclic adenosine monophosphate production in MMR14 was observed when co-cultured with MMR32, suggesting that soluble factors other than PTHrP produced by MMR32 were responsible for the inhibition of terminal differentiation of hypertrophic chondrocytes. This report is the first to show cell-to-cell interaction in the growth plate using cell lines, which will be useful material to investigate the regulatory mechanism of chondrocyte differentiation.
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PMID:In vitro demonstration of cell-to-cell interaction in growth plate cartilage using chondrocytes established from p53-/- mice. 1251 Aug 10


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